Concerted hydrolysis mechanism of HIV-1 natural substrate against subtypes B and C-SA PR: insight through molecular dynamics and hybrid QM/MM studies

It is well known that understanding the catalytic mechanism of HIV-1 PR is the rationale on which its inhibitors were developed; therefore, a better understanding of the mechanism of natural substrate hydrolysis is important. Herein, the reaction mechanism of HIV-1 natural substrates with subtypes B...

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Published in:Physical chemistry chemical physics : PCCP 2020, Vol.22 (4), p.253-2539
Main Authors: Sanusi, Zainab K, Lawal, Monsurat M, Govender, Thavendran, Baijnath, Sooraj, Naicker, Tricia, Maguire, Glenn E. M, Honarparvar, Bahareh, Kruger, Hendrik G
Format: Article
Language:English
Subjects:
Activation energy
Charge transfer
Correlation analysis
Enzymes
HIV Protease - metabolism
HIV Reverse Transcriptase - metabolism
HIV-1 - enzymology
Hydrogen Bonding
Hydrolysis
Kinetics
Lead compounds
Molecular dynamics
Molecular Dynamics Simulation
Protein Binding
Quantum Theory
Reaction mechanisms
Substrate inhibition
Substrate Specificity
Thermodynamics
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Summary:It is well known that understanding the catalytic mechanism of HIV-1 PR is the rationale on which its inhibitors were developed; therefore, a better understanding of the mechanism of natural substrate hydrolysis is important. Herein, the reaction mechanism of HIV-1 natural substrates with subtypes B and common mutant in South Africa (subtype C-SA) protease were studied through transition state modelling, using a general acid-general base (GA-GB) one-step concerted process. The activation free energies of enzyme-substrate complexes were compared based on their rate of hydrolysis using a two-layered ONIOM (B3LYP/6-31++G(d,p):AMBER) method. We expanded our computational model to obtain a better understanding of the mechanism of hydrolysis as well as how the enzyme recognises or chooses the cleavage site of the scissile bonds. Using this model, a potential substrate-based inhibitor could be developed with better potency. The calculated activation energies of natural substrates in our previous study correlated well with experimental data. A similar trend was observed for the Gag and Gag-Pol natural substrates in the present work for both enzyme complexes except for the PR-RT substrate. Natural bond orbital (NBO) analysis was also applied to determine the extent of charge transfer within the QM part of both enzymes considered and the PR-RT natural substrate. The result of this study shows that the method can be utilized as a dependable computational technique to rationalize lead compounds against specific targets. Graphical representation of the concerted acyclic transition model of an HIV-1 natural substrate using the two-layered ONIOM (B3LYP/6-31++G(d,p):AMBER) method.
ISSN:1463-9076
1463-9084
DOI:10.1039/c9cp05639d